In recent years China's legal system governing pharmaceutical research, production, and marketing has been substantially modified. The country has been working on streamlining regulations and aligning itself with international standards of practice. Clinical trial activity in China is increasing, and in accordance with World Trade Organization requirements. 

The first version of Good Clinical Practice (GCP) regulations was issued in 1998 by the Ministry of Health (MOH). After the establishment of the State and Drug Administration (SDA)—now the State Food and Drug Administration (SFDA)—the SFDA formally issued its GCP regulations on September 1, 1999. The latest version was issued in 2003 after both the new Drug Administration Law (2001) and the new Drug Registration Procedure (2002) went into effect. 

According to SFDA's data, the number of multicenter clinical trial applications in the first half of 2003 was almost as large as the combined total in 2001 and 2002. This may be an indication that multinational companies are recognizing the advantages of conducting trials in China. 

Conducting multinational clinical trials is a new phenomenon to China, and there are some local practices that differ from other countries, which  can affect the way trials are conducted. 

A multinational company conducting trials in China may face a number of issues, including a lengthy approval process (6–12 months), language barriers (oral and written), and the task of setting up a local central lab—export of whole blood/DNA is restricted or prohibited in China. In addition, qualified logistic support is limited (e.g., central storage, IVRS, fax line, broadband for EDC). As a result, multinational companies may have to rely on CROs familiar with local customs and practices. 

In China, only hospital centers designated by SFDA are authorized to conduct trials. The hospitals' principal investigators (PIs) often have extensive experience with Western companies. Domestic investigators also want to be involved in international multicenter trials. The investigators at the centers are well-known professors who have conducted research and published works, and are often members of the New Drugs Evaluation Committee and/or Drug Reimbursement Committee. 

China's regulations are often unclear and ambiguous. Since the investigators are relied on to interpret these regulations, they have a profound influence. Officials often follow their interpretations and act accordingly. Thus, the investigators have tremendous power in the drug registration and marketing processes. Communicating regularly with the PI to discuss data management and "shadowing" them to confirm that data is handled properly will avoid misinterpreting local trial results, thereby expediting the process. 

The SFDA is responsible for the evaluation and inspection of  clinical trials of new drugs. On February 19, 2004, SFDA issued a regulation specifying that all clinical trials should be conducted at GCP-compliant sites; those sites that did not have the GCP certificate were not able to conduct clinical trials after March 1, 2005. Presently, there are 242 GCP-compliant sites in China.

  However, SFDA is still checking out the old GCP-certified hospitals. If they do not meet the requirements, they will not be permitted to conduct clinical trials. 

Today, the number of GCP-certified hospitals does not support the increase in clinical trials and drug development. To meet the need for more sites, SFDA recently approved the establishment of some new ones and is reviewing new site applications for GCP compliance. Site names and their GCP-certified departments can be found on the SFDA Web site, which is mostly in Chinese (see Table 1 for an example of what can be found on the SFDA Web site). 

Although the search results indicate that there are many sites, the viewer will need local assistance to help them find out which ones will best meet their needs. For example, 86 sites can be searched for the indication of cancer,

  but only about 15 sites are highly experienced and well known. 

 Table 1: Sites capable of conducting cancer clinical trials.			

Multinational companies are conducting more multicenter clinical trials in China because of the ease of recruitment. In 2005, there were 1.3 billion people living in China.

  With one of the largest populations in the world and easy access to a treatment naïve population in large hospital centers, the time it takes to recruit patients is dramatically reduced.

  Access to such a large treatment-naïve population available to enter clinical trials may help companies speed drug development. 

At present, 80% of medical resources are allocated to the big cities, and 30% of that is focused on larger hospitals. Since more patients visit larger hospitals,

  treatment for major maladies is centralized to them (Table 2 lists the most common diseases of inpatients

 ). In the countryside, most of the peasants are afraid to see the doctor because of poor health insurance coverage; as a result, many of these patients are treatment naïve. This may be another source of recruitment, as free treatment will be attractive to low-income patients. 

Table 2. Percentage of top 10 diseases of inpatients in China (2003). 			

In addition to wanting to participate in clinical trials because of access to free medical treatment, the Chinese appear to prefer imported drugs over domestic drugs. They feel that the expensive drug is better than the cheap drug. 

Most Chinese subjects enroll in a clinical trial when they see a doctor or when they are hospitalized. If the investigator finds the patient meets inclusion/exclusion criteria, they try to persuade them to participate in the study after the patient is given some general information about it. However, the patient has the right to refuse the investigator's offer. One study estimates that in the United States, 66% of subjects enroll independently of their doctor.

  In China, almost 90% to 100% of subjects are offered enrollment by their doctor. This difference is important when preparing recruitment plans and materials. 

The cost of conducting clinical trials in China is relatively low, and the PI grant is generally cost-effective.

  For example, the average PI grant is $1000 USD for a cancer study excluding lab tests—it's roughly $2000 for the lab (see Table 3).

Logistics costs in China are relatively lower than in other countries (a meeting for 50 investigator attendees in China costs only $30,000 USD). And CRO fees are less compared to CRO fees in other countries. Many services cost less in China, but conducting clinical trials in the country requires the CRA to monitor the site more frequently since the site personnel are not well trained. The sponsor must also spend time visiting sites to conduct quality control work. 			

Sponsors should expect and prepare for language related misunderstandings during the planning and conduct of a multinational clinical trial. In China, almost all of the submission documents for SFDA and Ethics Committees (ECs) should be in Chinese, including the protocol, Investigator's Brochure, and Informed Consent Form—which can increase costs and time. Repeated feedback to correct errors in translating administrative and research documents also increases the time sponsors spend on a project. 

Clinical trials in China are closely regulated by the government and may only involve hospitals they designate. As mentioned, regulations concerning trials are the Drug Administration Law of 2001 and the Drug Registration Regulation of 2002. A set of new regulations was introduced in 2002, and in mid-2003 more changes were made by China's SFDA. Although some changes are intended to shorten approval timelines, obstacles still exist in the approvals process. 

On the positive side, Chinese drug policies are becoming more uniform. Changes introduced have focused on shrinking evaluation timelines to 100 working days.

  At the same time, because the government has adjusted their policy on multicenter clinical trials,

  multinational companies appear to have more confidence in the Chinese pharmaceutical market. 

However, if a company is looking to do a pivotal Phase III trial in China, there's still the question of whether they will have to conduct a Phase I PK/PD or Phase II trial there. Right now it remains on a case-by-case basis. It's a pity that China's SFDA still does not have mutual recognition with the regulatory authorities in other countries. 

For products that have not been marketed in foreign countries, Phase I, II, and III studies are needed when applying for a drug license. However, for such drug applications, a Phase I study must be finished in a foreign country; otherwise clinical trial approval might not be issued. This may be due to the fact that the Chinese regulatory authority and Institutional Review Board/EC still do not know how to find early risk patients. 

For drugs that have been marketed in foreign countries, if the Phase III trial application is submitted, Phase I or II studies may be omitted if the study data is from Eastern Asia, such as Korea or Japan. If the Phase I or II data is from the EU or United States, Phase I or II studies might be repeated in China. If the sponsor has the ability to lobby the regulatory authority, sometimes a Phase I or II study might be omitted. 

If a company does not have a manufacturing plant in China, the investigational product can be imported. However, this can be problematic due to regulations on importation. Every drug import has to be inspected, which can require 15 to 30 days. The National Institute for the Control of Pharmaceutical and Biological Products conducts inspections for imported drugs. If the sponsor has a manufacturing plant in China, they can use their local product to submit a clinical trial application. 

China is expected to be the fourth largest pharmaceutical market by 2012. Most of the leading international pharmaceutical companies have established (or plan to establish within the next two years) clinical trial facilities. AstraZeneca established a clinical trial center in Shanghai in 2002 and Pfizer established its Asia-Pacific Data Management Center in Shanghai in 2005.  

According to Chinese pharmaceutical annual statistics, the pharmaceutical industry reached $40 billion USD.

  Multinational companies and imported drugs account for more than 50% of industry earnings. The average growth rate in pharmaceuticals has increased by almost 15% per year since 1978.

  Factors contributing to this rapid growth rate are a population of 1.33 billion, 100 million people over age 65, urbanization, and an increase in GDP.

  It is estimated that the Chinese pharmaceutical market will reach $75 billion USD in 2010.

Each day a drug is delayed from market, sponsors lose up to $8 million.

  Chinese regulatory authorities' review time for a proposed trial is now six to nine months, but sometimes it can take 12 months. However, for a multinational clinical trial, the review process is accelerated.

  (Previously, marketing a new drug in China often took two to three years.) With the new legislation, conducting multinational clinical trials in China can accelerate the review process.

In practice, the EC should take full responsibility for examining the experimental design, the procedures to be employed, expertise of the investigators, and anything else that is important to the protection of the patient. Unfortunately, ECs rarely satisfy the requirements of GCP guidelines in China. 

Some sites in China have not established an EC, or the composition of the EC does not meet the requirements. Even if there is an established EC, most of them do not really know what their responsibility is. Some ECs will charge the sponsor when they review the submission. At present, most sites acknowledge the main EC's approval, so if there is a multicenter trial in China, after the main EC approves it the other sites' EC will not review it. However, the situation has greatly improved since the implementation of GCP. But it has by no means been an easy job getting everything on the right track since first implementing GCP seven short years ago. 

The present challenge lies in EC composition. Many trial sites have established ECs but they lack professional ethics. In addition, members do not have a clear understanding of the characteristics, tasks, and responsibilities of their job. Some ECs are mainly composed of directors from trial sites who emphasize the administrative and scientific aspect of trials. They do not deal with ethical, legal or social aspects. And frequently, members do not know how to review documentation. 

There is also considerable variation in the method of working with ECs in China. Often the EC cannot function independently, as most of its members work at the institution involved and may have a conflict of interest. For example, if a project belongs to the head of the institution, members of the EC may feel compelled to approve the proposal. 

It is becoming more evident that attention should be paid to strengthening ECs in China rather than pretending that all subjects in a trial are fully aware of what is going on and that informed consents are valid. All studies must be ethical, and the basic rights of all subjects participating in a trial must be protected. This could be achieved through an effective EC. 

The good news is China's SFDA drafted an IRB/EC regulation on August 23, 2006. The SFDA asked for comments on the draft: The Guidelines for Ethics Committees on Drug Clinical Trial Ethical Review.

  The draft includes and covers intensifying the supervision of trials, ensuring the rights and benefits of subjects, giving full play to the role of ECs in the ethical review of trials, and standardizing EC review of trials. The version should be finalized soon. 

Several of the well-established sites have a strong team of EC members, and they hold a monthly review that covers areas such as protocol design and the informed consent process. Team members question the protocol design if queries are made during review, and the decision may be issued a week later for either approval, rereview after amendment or disapproval. Usually, the EC meeting charges the sponsor a fee for each review, which the committee prefers to receive in an efficient manner. 

If the sponsor selects an influential PI at the hospital to conduct its trial, the PI will work hard to get the EC to review the site's application early. Today, most multinational clinical trial application drugs have been marketed in foreign countries. For those multinational trials, the data from outside China is persuasive when it comes to the application decision. 

Articles

Feature Article

Stricter regulations & low costs are attracting more multinationals to the country, but hurdles still exist.

Clinical Trial Opportunities in China

For the lay public, clinical research is not typically a topic of dinner table conversation. It's not discussed in high school science classrooms. And it's usually only discussed in a doctor's office when a patient has been diagnosed with an illness for which no available treatment exists or for which available treatments are unpleasant, unsafe, and ineffective. 

Yet arguably, clinical research touches every person's life regularly. According to the U.S. Census Bureau, more than half of all Americans (55%) are taking prescription medications at the present time. Most Americans (90%) report routinely using over-the-counter medications. And most Americans (85%) state that they recently read an article or heard press coverage of clinical studies recommending new approaches to improving health through diet, exercise, and lifestyle changes. 

The lay public simply does not realize or understand that all medicines it consumes—and many behavioral interventions—have gone through clinical testing, involving people who have volunteered their participation. Indeed, although the majority of people believe that clinical research helps advance medical knowledge, less than 15% believe they have even a rudimentary understanding of how clinical research affects them directly. 

Ubiquitous patient recruitment ads on metro trains, in big-city newspapers, on the radio, and in health communications bombard the public frequently. An estimated half a billion dollars is spent annually on mass media patient recruitment advertising and promotion. These ads are designed to recruit for specific studies, and yet it is clear that the broader understanding of the benefit of clinical research is neither widely considered nor appreciated by the public. For this reason, specific study messages are met with a large amount of indifference: They have no foundation on which to rest. The public has no context within which to understand the importance of clinical research. 

 This public service ad for CISCRP was rated highly among focus group members, beating out campaigns featuring sports stars.			

Extensive media coverage of drug withdrawals and their aftermath; conflicts-of-interest among FDA members and research professionals; questionable pricing practices; and tragic errors resulting in harm to patients have left the public confused and troubled. Public sentiment toward the clinical research enterprise is at an all time low. One recent public poll revealed that only 14% of the American public feels pharmaceutical companies are "Honest," a rating similar to that bestowed upon the tobacco and used car industries. In another 2006 poll, more than 70% of Americans said they believe drug companies put profits ahead of patient needs. 

The clinical research enterprise faces its greatest crisis ever: widespread distrust. Without public and patient support, there can be no realization of innovations in medical therapies. In the absence of study volunteers, clinical trials cannot be conducted or they are severely delayed and, ultimately, public health advances are not made. An alarmingly low 4% to 6% of eligible patients participate in U.S.-based clinical trials annually. 

The clinical research community has largely failed to respond to poor public perception and eroding public trust.  Professionals affiliated with research sponsor organizations, with service providers, educators, regulatory agencies, and human subject protection programs have been insular in their approaches to addressing the crisis. They have focused on better professional training, on accreditation and certification, and on improving the disclosure of conflicts-of-interest and the accessibility of clinical research information. But the magnitude of this crisis demands a response designed to educate the lay public and to "rebrand" clinical research as a valuable public good. 

Large-scale public education campaigns have proven to be a highly effective strategy for changing human perception. The long-running national milk campaign "Got Milk?" has used a string of celebrities to promote milk consumption. The "This is your Brain on Drugs" campaign, featuring those famous fried eggs, has affected at least two generations' views on the dangers of drug abuse. And who can forget the crying Indian, whose tearful face in the 1970s television commercials became a powerful symbol of the anti-litter, save the environment movement? 

Focus Group Reactions to Everyday Heroes			

Clinical research needs its own "Got Milk"-like campaign—one that is recognizable and easy to remember, and engages the public in thinking differently about clinical research. Such a campaign has been a top initiative at the Center for Information and Study on Clinical Research Participation (CISCRP) during the past 12 months. 

With an unrestricted educational grant from Eli Lilly and pro bono collaborative support from Fast4wD Ogilvy—a division of international advertising and marketing agency Ogilvy & Mather—CISCRP worked extensively with a large and diverse group of research professionals and patient advocacy organizations and conducted consumer focus groups to arrive at the most effective clinical research rebranding message: "Everyday Heroes." To a wide cross-section of the population, print advertisements that call out ordinary individuals as heroes piqued interest and curiosity in addition to sending the message that being a part of clinical research is a good and even noble thing to do. 

Other campaigns tested were less likely to get across the idea that an everyday person can help save lives. Those featuring study volunteer heroes alongside recognized sports heroes were polarizing and unpopular. Another campaign that used an eye-catching red superhero cape blowing on a clothesline was confusing to participants and some perceived the cape as trivializing the message of everyday heroes. A campaign picturing a long line of people coming together to advance medicine tended to raise more questions than it answered. Another showing remedies for everyday ailments was confusing and viewed by some as promoting homeopathic drugs. 

Like the "Got Milk?" campaign, "Everyday Heroes" will unfold nationally as a series of engaging, general educational messages. As such, one of the key challenges is to maintain a long-term perspective that the goal of the campaign is to build consumer awareness and trust in the important role that clinical research plays in advancing medical science, and to change public perception and appreciation of the clinical research volunteer. The purpose of this campaign is not to recruit volunteers into currently enrolling studies or promote newly approved treatments. This campaign must focus on early education and on establishing a relationship and a connection with the public. What follows is a detailed discussion about the development of the Everyday Heroes campaign. 

Eighteen months ago, CISCRP and Fast4wD Ogilvy convened a small diverse group in Washington, DC, to talk about the difficulties in patient recruitment and retention and how that related to public education failures. That initial meeting brought together about two dozen people representing patient advocacy groups, the U.S. Food and Drug Administration, the National Institutes of Health, PhRMA, the National Health Council, academic institutions, pharmaceutical companies, CROs, investigative sites, patient recruitment service companies, and the IRB community. Fortunately, the dialogue remained constructive, the views largely shared, and the mindset determined to move forward. 

This initial meeting highlighted the unified view that not only does the public feel disconnected to clinical research but also that those orchestrating trials often forget the process has an association with physicians in the community and involves real members of the public. There was also consensus that study volunteers deserve recognition and appreciation for the profound gift that their participation provides for others. Most study volunteers want to know that they're making a valuable contribution to science. Yet few research centers stay connected to volunteers after a trial has ended. 

At the conclusion of the small group meeting, Fast4wD Ogilvy reviewed attendee observations and suggestions and developed 15 different campaign ideas, called "Treatments." These treatments cut across a wide spectrum of educational approaches—some serious, some shocking, and some quite humorous, including one campaign that tried to capture how far advances in medicine had come. This campaign juxtaposed several old and new treatments, such as a pile of cow dung for severe skin burns against modern treatments made possible by millions of clinical research volunteers. 

Four months later, another meeting was held among nearly 60 research professionals representing all stakeholder groups involved in the clinical research enterprise. This large group spent a full day reviewing, discussing, and modifying the 15 treatments. At the end of the meeting, the group had winnowed the campaign choices to five. After incorporating suggestions and refining the campaigns to make them look polished and professional, the five treatments were presented in March 2006 to consumer focus groups. 

The focus groups included a representative mix of ages, genders, ethnicities, lifestyles, and occupations, and individuals were grouped into one of three socio-economic classes. The "Everyday Hero" campaign scored significantly higher across the board. Consumers liked the concept and felt appreciative of the people featured in the campaign. Also, the hero ads most prompted them to want to learn more. Among the lower socio-economic group, in particular, respondents identified with and admired the featured "Heroes." 

The copy on the final version of the campaign reads, "Medical heroes can be found in ordinary places. Together we can make a difference through medical research." Based on the request of many focus group respondents, the campaign also gives viewers a telephone number and a Web site where they can learn more about the clinical research process. 

"Everyday Hero" campaigns will make their debut in a broad public service campaign being targeted for launch in 2007. Heroes still under consideration for the other two ads include a person working behind a desk in an office setting, a teacher in an elementary school classroom, and a senior citizen in a social setting. The CISCRP logo and contact information will appear on the ads. The FDA has expressed interest in having its logo on the campaign material. 

Our goal now is to raise $750,000 to $1 million from leading pharmaceutical companies and government agencies to underwrite first-year campaign costs. The ads will run on a discounted basis in major consumer publications like 

 as well as on billboards, bus shelters, and bus backs in high traffic areas like Manhattan, Chicago, and Los Angeles. Banner ads will likely also be placed on commercial Web search engines and high-traffic consumer sites like Yahoo and WebMD. 

CISCRP and Fast4wD Ogilvy intend to conduct follow-up research on the campaign's impact on public perceptions about and public interest in clinical research. Over time, provided that this campaign achieves the reach and frequency planned, we're hopeful that ongoing public opinion will reflect a better-informed populace, greater appreciation of the value of clinical research to public health, and deeper recognition of research volunteers. 

The authors wish to thank David Davenport-Firth, director of Ogilvy Healthworld, for his creative leadership in developing this campaign. 

 MS, MBA, is a senior research fellow at the Tufts Center for the Study of Drug Development and the chairman of the Center for Information and Study on Clinical Research Participation, both in Boston MA, (617) 590-4175, email: 

 is group managing director of Ogilvy Healthworld in London, UK. 

 is the director of global enrollment optimization at Eli Lilly and Company, Indianapolis, IN.

*To whom correspondence should be addressed.

A new patient recruitment campaign depicts trial volunteers as heroes and aims to both educate and win over the public.

Mission Possible: Rebranding Clinical Research

Let's propose that in clinical development, investigators are suppliers. If this is the case, then sponsors can use supply chain management principles to help guide their relationships with investigators. Based on this proposal, the following article explores five supply chain management principles that have relevance for clinical development and specific ideas for how sponsors can apply them. 

Supply chain management principles have usually been associated with manufacturing processes and therefore have not typically been applied to the process of clinical drug development. Clinical development professionals, after all, do research; they do not produce anything that requires raw materials from external suppliers. Instead, they collaborate with private physicians to conduct studies. If a new product is proven to be safe and effective, they pass the product over to their manufacturing colleagues who then need to worry about how they will work with suppliers to acquire the materials they need to make the product. 

However, a closer look at the clinical development process reveals more parallels with manufacturing than first meets the eye. Like any process, clinical development has inputs, internal processing, and outputs (see Figure 1). Inputs are the new product candidates from preclinical research. Throughputs are the studies that development professionals design and conduct. Outputs are the clinical study reports that eventually become components of a marketing application. Hence, the mandate of clinical development is to "manufacture" clinical study reports. 

Looking at the process from a supply chain perspective, clinical development can be viewed as a company with suppliers and customers (see Figure 2). The supplier is preclinical research (and/or the licensing department), and the customer of clinical development is the regulatory agency that eventually grants permission to market the product. 

Depending on how the larger pharmaceutical, biotech, or device company is organized, clinical development's customer might be an internal regulatory affairs or regulatory submissions department whose specific responsibility is to keep abreast of the customer's (the regulatory agency's) requirements and to ensure that clinical development's product meets those requirements (see Figure 3). 

In any case, for clinical development to "manufacture" their products (i.e., clinical study reports), they are dependent on a system of suppliers. 

Without question, the most challenging suppliers in need of management in this process are clinical investigators. This is not to suggest that physicians operate only in the role of investigators. They are of course still physicians, concerned primarily with providing quality care to their patients. However, when physicians take on the role of investigator they agree to provide the data that will become the essential raw material of a clinical study report. 

Given the complete dependence of clinical development on a reliable supply of accurate and timely patient data, one would expect a dedication of resources commensurate with ensuring that every potential contributor to a win-win relationship with the investigators/suppliers is in place. Amazingly, however, investigators are typically the most undermanaged component in the clinical development supply chain. 

Undermanagement is not necessarily intentional. Rather, it seems to be a case of unawareness of supply chain management principles or a reluctance to apply the model to a scientific research endeavor—as though application of a business model might somehow jeopardize the integrity of the science. 

Another reason for the absence of supply chain management principles in clinical development is confusion over the role of investigators. For example, the clinical development organization of one top five pharmaceutical company did not view investigators as suppliers but as customers. The confusion is somewhat understandable: Investigators are potentially prescribing physicians—one of the company's ultimate customers. However, treating investigators as customers during clinical development is like Toyota treating its tire supplier as a customer because they want the tire supplier to buy Toyotas. Listening to the voice of the customer is a fine idea, but it does not really apply when the "customer" is a supplier. 

If clinical development sponsors were to look to supply chain management for guidance on how to manage their relationships with investigators, they might find some very applicable pieces of advice. What follows is a sampling of supply chain management principles and examples of how these principles might be applied to clinical development. 

One piece of supply chain management advice is to create a win-win situation between the company and its suppliers.  This is largely achieved through a contractual framework. Contracts or agreements should be structured so that when the terms of the agreement are met, both the company and the supplier get what they each need. 

All clinical development sponsors negotiate contracts with their investigators, usually on a study-by-study basis. Typically the sponsor has established standard fees for clinical procedures, which are rolled up into per visit or per patient totals. Contract negotiations are then largely a matter of sponsors trying to pay less while investigators vie for more. A best case scenario outcome for these negotiations is for the sponsor to pay slightly less for some procedures and for the investigator to get slightly more for others. Then, both parties feel as if they won part of the negotiation. 

Granted, money is an important component in establishing a win-win situation between sponsors and investigators. Ultimately, both sponsors and investigators need to make a profit. But is there a way for sponsors to structure payments so that the better an investigator performs the more money they receive, while at the same time keeping the overall cost of the study for the sponsor within budget? We believe there is, and we will return to this issue later in the section entitled "Create a relationship between compensation and performance." 

Apart from money, are there other factors that can contribute to establishing a win-win relationship between sponsors and investigators/suppliers? Are there things besides money that investigators need or want from participating in a clinical trial? The only real way to answer that question is to talk with individual investigator candidates. Potentially, an investigator might consider the following outcomes as "wins": 					

Having the opportunity to be an expert presenter at a medical conference

Becoming an expert consultant on future protocols

Being invited to join an elite group of the sponsor's "preferred investigators"

Being listed as an author on published study reports.

Assuming that the development product makes it to market, all of these things are obviously wins for the sponsor as well, and any of them could be included in negotiations. 

None of this focus on establishing a win-win situation is intended to overlook the fact that for many sponsors and investigators, the most significant and satisfying win occurs when a product proves to be of real benefit to patients. 

Another piece of advice from supply chain management: Provide clear and detailed specifications to suppliers. Most clinical development professionals probably think they do this by writing study protocols and providing tools to record patient data (i.e., case report forms or electronic data capture systems). In fact, sponsors are required by law to not only develop protocols but to also train investigators and study nurses on how to conduct the study. The typical method for training investigators and their staff is to hold a one- or two-day meeting during which time the sponsor delivers a series of lectures on protocol-specific and GCP requirements. 

Although sponsors write protocols and hold investigator meetings, they are invariably plagued with data discrepancies, protocol violations, and delayed patient enrollment. All of these problems are expensive to fix and in some cases can even render the study data unusable. So what makes these defects occur with such relentless frequency? The problem is multifaceted. Part of it lies not in the lack of clarity or detail, but rather in the way the specifications are communicated. 

Investigator meetings are clearly inadequate. A large percentage of investigators do not even attend the meetings. In one recent 70 site study conducted by a large pharmaceutical company, only 18% of the investigators attended the investigator meeting. For those investigators who do attend meetings, sponsors typically make no attempt to assess whether they actually understand the study specs presented. Furthermore, even if they understand the specs, it can be anywhere from one day to three months (or more) before the investigators screen their first patient. At this point, it is unlikely that they will remember the details of what they are supposed to do. 

Recently, supply chain management experts have been advising companies to establish more open, real time communication channels with their suppliers. These communication channels can be used to meet a variety of information exchange needs, including information on specifications. 

It is now relatively easy and inexpensive to create a secure Web portal through which clinical development professionals can initially deliver training on protocol specifications to investigators and study nurses. The information can remain available on the portal 24/7 for study staff to access whenever needed throughout the duration of the study. And if the specs change, as frequently happens with protocol amendments, the changes can immediately be posted on the portal. In addition to being easy to post, training modules can easily be used to test the learner's comprehension of the material and track successful completion of protocol-specific or GCP training. 

Sponsors and regulators alike are beginning to recognize the inadequacy of the traditional approach to delivering study specifications. After an investigator meeting, the sponsor ends up on an attendee list. The list tells the sponsor and regulator nothing about whether the attendees actually learned anything at the meeting. On the other hand, by delivering protocol-specific training via the Web, the sponsor can easily end up with a list of investigators and study coordinators who have demonstrated their understanding of study procedures. 

Requiring medical professionals to become "certified" in specific procedures is certainly not a novel concept. After all, physicians do not earn medical degrees simply by attending classes at medical school. They must pass the exams. 

The use of Internet/Web technology can indeed improve the way sponsors communicate study-specific requirements. 

Supply chain management experts also point out the importance of up front clarity regarding defects in materials. Suppliers need to know how the company defines a defect, how defects will be measured, and how defects will be handled. 

In clinical development, sponsors contract with investigators to supply patient data in an agreed time frame. Rarely, however, are sponsors specific about their definition of defects or the steps that will be taken if defects are unacceptable. Obvious data defects include missing information, errors, and inconsistencies. But the definition of what actually constitutes an error needs to be spelled out. Data management departments are notorious for sending questions back to the investigator for resolution. Does every question sent to the investigator signify a defect? Are GCP or protocol violations considered defects? What about missed deadlines? 

Defining what constitutes a defect and how defects will be counted is only important when there are consequences to the supplier related to the number of defects. 

This leads to a fourth insight from supply chain management experts: Create a relationship between investigator compensation and investigator performance. 

Let's say Investigator A enrolls patients not only on time but also ahead of schedule and is actually ready to enroll more patients if given the okay. In addition, informed consent is correctly obtained and documented for each patient, and the data the investigator submits has a defect rate of less than one per thousand. Investigator B, on the other hand, is several months late in enrolling patients, the informed consents frequently have date or signature problems, and when the data are finally submitted there is an average of three defects per patient visit. 

Subsequently, the sponsor will need to spend far less on Investigator A than Investigator B in terms of correcting errors and monitoring patient enrollment. Should Investigator A get paid the same amount per patient as Investigator B? While the answer seems obvious, most sponsors pay high performers and low performers the same amount. 

So why aren't sponsors creating a relationship between  compensation and performance? One sponsor did not want to be bothered with creating the tracking system required for measuring investigator performance. This concern seems  rather insubstantial since most clinical data systems already have the information needed to assess investigator performance. All that is required are some computer programs to extract and report the required information. 

Another sponsor did not want to relate compensation to performance for ethical reasons, wary that paying more for clean data and fast enrollment might induce investigators to submit "favorable" data or enroll unqualified patients. The sponsor was also worried about how regulators would view relating compensation to performance. Again, this concern  seems rather insubstantial and superficial. 

First, in placebo-controlled clinical studies, it would be very difficult if not impossible to provide "favorable" data. Even in trials that are not blinded or placebo controlled, there remains a clear distinction between error-free data and "favorable" data. Error-free data are data that have no missing values, no recording errors, no illegibility, no inconsistencies across data fields, etc. "Favorable" data, on the other hand, are data that are modified to give the impression that the product is more safe or effective than it really is. In short, it is fraud. 

Applying supply chain management principles to clinical development can save sponsors money and time.

Investigators as Suppliers

When it comes to subject recruitment, every clinical trial professional faces a grave dilemma: Suitable individuals who meet the study criteria clearly need to be informed about the benefits of taking part in a trial, but to what extent is it appropriate for an investigator to actively urge people to participate in clinical research? In other words, when does acceptable encouragement become harassment? 

 Jenny Hewison, Professor of the Psychology of Health Care, Institute of Health Sciences and Public Health Research, the University of Leeds 			

This ethical dilemma is particularly acute in the United Kingdom, where government-owned hospitals in the National Health Service (NHS) provide around 90% of health care. Investigators must adhere to strict regulations. They cannot advertise for subjects because that is regarded as an inducement, and they are not supposed to refer to favorable results or publicity because that is viewed as promoting the research cause. Posters in clinics can indicate that a trial is taking place and investigators can obtain publicity by giving media interviews, but more overt methods are not permitted. 

 has added fuel to this hotly contested issue.

  The authors suggested that the practices of ethics committees in the UK are hindering subject recruitment. Lead author Professor Jenny Hewison from the Institute of Health Sciences and Public Health Research at the University of Leeds recently shared her views with Philip Ward, 

Q. In what ways are current research ethics requirements compromising the scientific quality of health research?

The problem I am most aware of relates to restrictions on how researchers may approach potential participants, and the effect those restrictions are having on recruitment rates and bias. 

For instance, let's say you get a letter from your general practitioner or hospital doctor giving information about a research project in which you might participate. Under the so-called opt-in system, the letter will make it clear that it is up to you to contact your doctor to say the researchers may contact you. You may also contact the research team directly. In contrast, under an opt-out system, the initial letter will explain that a researcher will contact you, usually by phone, unless you tell your own doctor that you do not want to be contacted, in which case your name will never be given to the researchers. 

In the UK, a trial to compare recruitment rates under the two systems cannot be conducted because one of the "treatments"—having to opt out of initial contact—is considered unethical. The best evidence we have for an effect comes from other comparisons of survey response rates, supported by a large methodological literature on factors affecting response and participation rates in research of different kinds. 

In many cases, trial participation rates seem to be falling. This may be due to attitudes toward "volunteering," an understandable lack of public awareness about the importance of response rates, incorrect assumptions about what research entails, and just plain inertia. We do not have the evidence to know for certain. 

Q. Are you also suggesting that only the researcher should deal with consent forms and the patient?

No, because opt in and opt out do not refer to participation in the research, only to being contacted by a researcher. Under both systems, the researcher seeks informed consent for participation in the research in the usual way. 

Information and consent forms have always had to be approved by the relevant ethics committee, under both systems. For good reasons, these documents have to be simply written and brief. They cannot possibly provide answers to all the questions that potential participants may wish to ask. A conversation with a researcher provides an opportunity for people to ask the questions that matter to them. 

Is such a conversation also a vehicle for talking somebody into something to meet a recruitment target? That is not as tempting as you might think. Signing up people who vote with their feet and drop out of the study soon afterward is a waste of everybody's time. Such practices would show up in retention rates, and corrective action would be taken. 

 article, you recommend that all patients are told about the potential use of personal information for research and that a strategy is needed to inform people about how research can contribute to improved health care. What exactly should patients be told, and how should this information be disseminated and written for the public?

Members of the public value health research but probably have a limited idea about the kinds of activities that are encompassed by it, and an even more limited idea about the kinds of things that threaten research quality. In the UK, the NHS could publicize much more strongly that it needs and values many different kinds of high-quality research because of the benefits it brings to patients. Publicity takes lots of forms, but with the right expertise, I am sure we could put together a good campaign if the will was there. 

If everybody benefits from research, it can then be argued that everybody should be encouraged to at least consider taking part if invited. Provided proper accreditation and safeguards exist, researchers could approach NHS patients to discuss participation in relevant projects, unless the patient had specifically asked to be exempt. Detailed information would be provided as required, but the initial "headline" message to anybody using the NHS would be about the importance and value of research, and the importance and value of considering participation. 

It would certainly help if investigators and sponsors were both involved in the campaign to raise and maintain the profile of research. 

Q. Will your proposed changes add to the work of an investigator or raise confidentiality issues?

Overall, the changes would lead to less work for investigators. At the moment, potential participants have to be identified and approached, but a low recruitment rate means that a lot of work is wasted. Extra clinics may then be needed to meet recruitment targets, but adding clinics means extra paperwork. If the new clinics have the same low recruitment rate, then a dispiriting cycle continues. 

To maintain confidentiality, NHS staff identify and make the initial contact with potential participants under both opt-in and opt-out systems. In theory, they could make telephone calls as well as send letters, but few have the resources to do that. To ask NHS staff to spend a lot of time on recruitment is also asking too much. The only people with both the time and the detailed knowledge to help people make informed decisions about participation are the researchers. If people who want 100% privacy can opt out, and if the researchers are vetted, accredited, and working to a tightly monitored protocol, then a balance can be struck between confidentiality and quality. We should explain to the public about the need for a trade off and consult with them about where they think the balance should lie. 

Q. The serious adverse events in the Phase I trial conducted at Northwick Park Hospital caused widespread public concern in Spring 2006. What impact do you think this case will have on recruitment rates, both in the short and long term?

We expect recruitment rates to be affected, but we need to wait and see the figures. If recruitment falls, proper research would be needed into the reasons behind that. When referring to clinical trials, the press gives the wrong impression that they are all the same, but members of the public can distinguish between different kinds of interventions pretty well, given the right information. They also know that trains can crash and ferries can sink (i.e., disastrous things can happen), but the right response is to work very hard to ensure they don't happen again. I have even heard it said—by a participant—that now is a good time to enter clinical trials because investigators are going to be ultra, ultra safety conscious. 

Q. What other general advice do you have about improving recruitment?

Recruitment is everybody's business, not just an investigator's. My best advice is to put yourself in other people's shoes and try to understand why someone might want to participate in a trial and what might put them off. A lot of it comes down to appreciating that before people decide what to do, they first try to make sense of being invited. Then they try to work out the implications for them personally. We need to help people carry out these tasks accurately and easily. 

1. J. Hewison and A. Haines, "Overcoming Barriers to Recruitment in Health Research," 

In this Q&A article, Professor Jenny Hewison of the University of Leeds shares her views on improving subject recruitment in the UK.

The UK Debate over Recruitment Strategies

Thanks to a focus on productivity and cost reduction within the pharmaceutical industry, along with a prevalence of Six Sigma-inspired improvement efforts, metrics are on a lot of people's minds. In fact, one might argue that metrics are on too many people's minds. Consider the following situation, where you are collecting data to track cycle times for processes within your area of responsibility. 

At some point you're talking to a colleague about the idea of creating a handy dashboard to display all of your key metrics in one location. Your colleague, having some experience with dashboards, sends you a prototype of one she's working on in her department—and it contains much of the same data you have been painstakingly collecting over the past several months. Worse, there are discrepancies between your numbers and hers. 

This story is undoubtedly all too familiar within many departments in clinical R&D, an area that has only recently begun to develop a true operations mindset. Most, if not all, managers of R&D departments recognize the criticality of collecting data and tracking the performance of their many processes. However, many of these efforts are disjointed, inefficient, and misguided. Conflicting reports, duplication of efforts, and misapplied metrics plague many companies' attempts at making sound data-driven business decisions. The creation of a central metrics group can go a long way toward eliminating wasted effort and drastically increasing the value of an organization's data. 

Before thinking about how to create a central metrics group, one must first ask why they should create one. Is it even necessary? The answer, of course, varies from situation to situation. 

Certainly all companies, regardless of industry, should adopt a continuous improvement mentality, meaning that metrics should play an important role in just about every business. But a number of factors will help to decide whether or not a central group is appropriate. Company size is one, as larger companies will typically benefit more from such an arrangement by consolidating voluminous amounts of information and reducing duplication of efforts. A company's technological maturity is another key factor, as central metrics groups tend to rely heavily on an advanced technological infrastructure for the collection of data and dissemination of information. But perhaps the most important factor is the overall corporate strategy. 

The degree of commitment among top levels of the organization with regard to continuous improvement and their views on how it should be accomplished will ultimately be the deciding factor.  Companies with a high level of commitment toward improvement will take the time to seriously consider whether or not a central group will work best for them. For many, the benefits of increased efficiency and consistent reporting of data will outweigh the bureaucratic headaches that come with setting up such a group. 

Too often, metrics are collected largely for the sake of collection. Alternatively, metrics are utilized by individual departments to make their lives easier (e.g., to keep tabs on things out of mere curiosity) or are measured against self-imposed yet meaningless targets. This often leads to localized optimization within the R&D value stream and a misalignment with other departments and perhaps the whole organization. 

For example, many clinical operations groups focus on the cycle time from protocol approval to first-patient screened. In the long run, does it really matter how quickly one site begins enrolling patients? The critical measure—the one that speaks to the flowing of data to the next step in the clinical development value stream—is when all sites finish enrolling. 

This example demonstrates the "management by intuition" approach that seems to run rampant throughout the clinical R&D space. Years of experience, although inarguably valuable, seem to be commonly used as a substitute for hard data as opposed to a supplement. The sooner that clinical departments recognize the fact that metrics can be used to validate intuition and unearth previously hidden trends and root causes, the better off their decision making will be. 

Regardless of how a company structures its metrics function, corporate vision should set the context for performance measurement.

  (Figure 1 shows one possible strategic management framework.) Such a framework assures that performance measures align from top to bottom, which in turn puts focus on metrics that show how well value flows through the value stream. A central metrics group can do a much better job of maintaining this type of framework than disparate entities can due to the coordination inherent in the structure of a central group. It should be part of the central group's mission to keep metrics in alignment. 

In order for a central metrics group to be effective, it must have a thorough understanding of both the business and basic analytical methods (in order to properly determine root causes of problems, etc.). To this end, it is often worthwhile to create a group utilizing staff from a variety of areas, such as clinical, operations, and data management. Ultimately, the skill requirements will be based on the central group's scope, which needs to be defined early on. For example, will the group only handle late-stage development processes or everything from discovery through product launch? 

The next critical responsibility for the central metrics group is defining key performance indicators. For any given process, there should only be a handful (no more than five or six) and, more importantly, they should speak to the true nature of performance in light of the higher level objectives. Therefore, an organization ultimately concerned with productivity should lean toward metrics on outputs (e.g., patient visits processed) and resource allocation (e.g., FTEs utilized). An organization whose primary goal is to shorten time to market should focus on selecting key milestones that will help it manage business from a speed standpoint. Ideally, the central group will work with members of the respective functional areas to define the key performance indicators (see Figure 2), thus keeping metrics in alignment while still satisfying the business need for useful management reports at the operational level. 

Defining key performance indicators (see Table 1) requires a detailed understanding of not only the process at hand (having process maps to work with is obviously helpful), but of the suppliers of the inputs (data) as well as the customers' requirements for the outputs (dictated by what they plan on doing with the information they receive). 

Table 1. Examples of key performance indicators. 			

A central metrics group can potentially have many different customers from all areas of the organization. Identifying critical-to-quality requirements for these customers is the first step in defining a data collection, analysis, and reporting process that satisfies customer needs in the most efficient way. Critical-to-quality requirements might center on the timeliness of the reports (how real time the data needs to be), the level of detail required (e.g., the patient visit level), drill down capabilities (going from protocol level to visit level), ease of use, and accessibility. 

Keeping the critical-to-quality requirements in mind, the group must then identify sources of data and evaluate the underlying system's ability to provide that data on a just in time basis. Where required key performance indicators data is not available (or where the current system will not adequately support the new metrics process), a decision must be made to either implement a new system to collect the data or to alter or eliminate the key performance indicators—keeping in mind that doing so may compromise the effectiveness of the metrics program. 

Next, the methods for refreshing and distributing standard metrics reports must be determined. Typically, this will involve automation of data collection, the use of company intranets, and other tools that allow the ultimate customer to pull the reports whenever they need them. These real time reports and the expectations surrounding them must be carefully planned early on to avoid customer frustration later. 

Metrics reports are of little use, of course, if they are not accurate. It is therefore important to implement controls (mistake-proofing) and checks (quality assurance) within the process to ensure accuracy of information. For example, using a clinical trial management system that makes users select inputs from drop down lists reduces the chance of data entry errors. Having the system prohibit the user from moving to the next screen before all required fields are filled in can greatly help eliminate gaps in data. Automating queries of metrics data can also provide systematic stability to the process. Meanwhile, a gate review system on data quality and whether or not the final report meets the critical-to-quality requirements will further reduce the chances of the customer being dissatisfied. 

Clearly, ensuring accuracy is one of the most important jobs of the central metrics group. As such, a significant amount of time should go into the planning, implementation, and continuous improvement of the metrics QA/QC process. 

One final distinction in the development of a metrics reporting process must be noted. The standard reports mentioned earlier refer to those reports that contain the agreed to key performance indicators, have a standard design, and are simply refreshed on some recurring schedule as dictated by business needs. Users are also likely to request ad hoc reports from the central metrics group. Although the general process for gathering and reporting data will be largely similar, creating ad hoc reports is a far more resource intensive task due to the volume of requests, difficulty in finding data, complexity of the requests, and the need for additional quality checks. It is recommended that these types of requests be scrutinized by the central group to determine if there is legitimate business value in addressing them and, if so, how they should be prioritized. 

Once the processes have been defined, work can begin on creating the organizational structure of the central metrics group. By identifying all tasks that make up the new processes, an estimate of required resources can be made.  One uncertainty here is the volume of ad hoc requests that the group will need to support, which needs to be addressed with the group's executive sponsor ahead of time. 

Next, determine if new job descriptions need to be created or if tasks should be assigned as parts of existing job descriptions. Again, this will largely depend on the level of commitment and support from senior levels in the organization. It is critical that the proper amount of resources be dedicated to setting up the central group or it may be doomed to failure. 

Once the job roles are made clear and line and staff responsibilities identified, relationships between process owners and the central metrics function should be defined. For example, will the site management process owner be assigned one particular resource in the metrics group (the expert in that area) or will the group lead assign a resource based on availability?  Clearly, the more flexible the group is with its resources, the better it will be able to handle the flux of incoming work. 

Another consideration in creating the new group is how process improvement projects will be identified and executed.  Within a management framework such as Kelvin and Cross's Performance Pyramid mentioned earlier, the central metrics group will produce items of integrated financial and nonfinancial information that operating managers can use as a catalyst for process improvement.

  How much involvement should the central group have in these process improvement efforts? Although obviously a valuable resource for such activities, care must be taken to not overwhelm the central group and distract it from its core mission. 

Lastly, a final organization chart needs to be created for the central metrics group so that the structure and relationships are clear to both those internal and external to the group. 

It is quite likely that the establishment of a central metrics group will be a radical shift for most R&D groups. Regardless of how much effort is put into creating the processes and structure of the group, if people are not aware of the new group and how it will function—and, most importantly, how it will benefit them—it will wither and die. 

As usual the best place to start is at the top, by gauging the level of executive support for the group. Is the effort being trumpeted by the highest levels of management as a showpiece of their effectiveness and innovation? Or has the green light been tentatively given with a wait-and-see attitude? The amount of drum beating required at the ground level (i.e., departmental communications, informational presentations, informal meetings with key personnel, etc.) will be determined by the answer to these questions. 

If the higher-ups are trumpeting the effort, it's likely that most people will get on board—whether they want to or not—without having to be pushed too hard. If, however, they are tentatively giving approval, some serious consideration needs to be given to how the new group will be marketed to the larger organization. As mentioned, showing people what's in it for them will make all the difference. If others within R&D can be convinced that they can get what they want when they want it, and with little or no effort on their part, the central metrics group will be on its way to organizational acceptance. 

Having an idea of high-level support, the next step is to go about identifying all stakeholders and engaging the key ones in developing implementation plans and identifying potential obstacles. This not only provides additional buy-in from key stakeholders but can eliminate potentially serious problems before they have a chance to derail the new group. Developing and executing a communication plan is critical (i.e., who gets what information, how frequently, and in what form). People in the organization, especially key stakeholders, need to know what's happening at all times so they feel connected to the change and also so they can communicate back issues or concerns they may have. Again, the voice of the customer needs to be kept in the forefront of everyone's mind; the central group lead should be mainly concerned about adding value, and value is always defined by the customer. 

Finally, training programs need to be developed, not only on the new processes but also on how to use the new reports.  It cannot be assumed that all end users will automatically understand what they are supposed to do with the information that will be available to them. The end goal is to enable better business decisions, and all personnel need to be shown how the new reports (and the central metrics group as a whole) will help them reach this goal, and what limitations exist. 

Many promising initiatives fail in the implementation stage. Too often, everyone is so relieved that the solution is in place that they fail to support it when it counts: at rollout. The key issues at this stage involve managing the new process and workload, fielding questions and concerns, and tweaking the new process as needed. While this is largely the responsibility of the central group lead, having the support of key stakeholders (as discussed previously) can be extremely helpful in addressing any issues that arise while at the same time minimizing damage to the credibility of the new group. 

This article has shown the high-level steps that need to be taken in the establishment of a central metrics group. The more detailed steps will of course depend on the answers to the high-level questions raised throughout this article. But perhaps the most important part of the whole process occurs in the beginning, at the point when the decision is made to undergo such an endeavor in the first place (see Table 2). 

Table 2. Benefits and risks of establishing a central metrics group.			

As stated earlier, it is critical to maintain a top-to-bottom alignment of performance measures as strategic goals are linked to operations by translating aggregate market and financial goals into operational terms.

  The drive to create a central metrics group should be based strictly on the need to make better, faster decisions within this context. 

The justification should be based on a business case that clearly states that the value in establishing a central metrics group far outweighs the costs. Even though pharmaceutical companies exist in an industry founded on science, they are businesses at heart and need to be run as such. 

There are many secondary benefits in setting up a central metrics group. Metrics always need to be actionable, and meaningful key performance indicators can be used to create high-level scorecards and tactically manage studies or smaller processes. Creating baselines on which to base future improvement efforts, establishing a repository for organizational knowledge, and identifying and communicating best practices are all crucial in adding value to the organization. 

There is also the possibility of measuring the company against external benchmarks, but this author tends to agree with the comment by Womack and Jones: "To hell with your competitors, compete against perfection by identifying all activities that are muda [waste] and eliminating them."

  Regardless of one's views toward benchmarking, it is clear that what data is available for comparison is selectively shared, due to either a desire to avoid giving away too much or a reluctance to participate in the sharing of metrics via one of the existing benchmarking companies. 

Many factors contribute to the success of a company's metrics group, including high-level support.

Creating a Successful Central Metrics Group

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